Malignant gliomas are the most common and deadly type of brain cancer, highly invasive and resistant to radiation and chemotherapy. Our goal is to understand and target the mechanisms that drive tumor invasion and promote survival in glioma cells. In recent work we identified and characterized a novel extracellular matrix (ECM) protein named fibulin-3, which is absent in normal brain but is abundant in gliomas and promotes tumor growth and invasion. From our preliminary results, we hypothesize that fibulin-3 acts as a diffusible factor in the ECM, promoting invasion and cell survival by mechanisms that may include activation of anti-apoptotic Notch signaling and the NF-kappaB pathway, increased expression of pro-invasive genes, and controlled degradation of the extracellular matrix. Accordingly, inhibition of fibulin-3 may reduce tumor invasion and make gliomas more sensitive to chemotherapeutics. To test these hypotheses, in Specific Aim 1 we propose to investigate the mechanisms by which fibulin-3 promotes tumor cell migration and survival. We will analyze the mechanisms of activation of the Notch pathway by fibulin-3, and the requirement of Notch signaling to mediate the effects of fibulin-3 on cell invasion and survival. In Specific Aim 2 we propose to analyze the mechanisms by which fibulin-3 may promote ECM degradation. We will analyze if fibulin-3 increases metalloprotease activity and degradation of the ECM by activating the pro-invasive NF-kappaB pathway and inhibiting the metalloprotease inhibitor TIMP3. Finally, in Specific Aim 3 we propose to evaluate the impact of suppressing fibulin-3 on tumor progression and response to chemotherapy. We will assay a novel system to induce the downregulation of fibulin-3 in the tumor and will analyze the effect this downregulation on tumor growth, invasion, animal survival, and sensitization of gliomas to a standard-of-care anti-neoplastic drug. Successful completion of these studies will establish the role of fibulin-3 in brain tumors and will provide new insights into the mechanisms that support brain tumor progression. These results may translate into novel strategies to disrupt tumor invasion and achieve more effective therapies. PUBLIC HEALTH RELEVANCE: Malignant brain tumors, known as gliomas, are one of the types of cancer with worst prognosis. This situation has not improved even after decades of research because these tumors resist conventional chemotherapy and escape novel therapies, thanks, in large part, to their ability to infiltrate in the brain. We propose to characterize and target a novel protein that is secreted by glioma cells but is absent in normal brain. This protein promotes brain tumor invasion and tumor survival, which are the two key processes that reduce the efficacy of current treatments. Therefore, our proposed research is highly relevant because it may lead to effective disruption of tumor progression and increased sensitivity of the tumor to conventional chemotherapeutics. We believe that these studies will have relevance for the development of more effective strategies and therapeutic reagents against malignant brain tumors.